Extracorporal Cytokin Removal in Septic Shock: a Prospective, Randomized, Multicenter Clinical Trial

Phase 3

Suspended

• Conditions: Septic Shock
• Interventions: Combination Product: Standard medical therapy; Device: Standard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 24 hours; Device: Standard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 12 hours

• Registration Number: NCT04742764
• Lead Sponsor: University of Pecs

Brief Summary

Sepsis and septic shock have mortality rates between 20-50%. When standard therapeutic measures fail to improve patients' condition, additional therapeutic alternatives are applied to reduce morbidity and mortality. One of the most recent alternatives is extracorporeal cytokine hemoadsorption. One of the most tested devices is CytoSorb, however, there are a lot of open questions, such timing, dosing and of course its overall efficacy. This study aims to compare the efficacy of standard medical therapy (Group A, SMT) and continuous extracorporeal cytokine removal with CytoSorb therapy in patients with early refractory septic shock. Furthermore, we compare the dosing of CytoSorb adsorber device - as the cartridge will be changed in every (12 Group B) or 24 hours (Group C).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-01-26
• Study First Submitted QC: 2021-02-03
• Study First Posted: 2021-02-08
• Status Verified: 2023-04
• Last Update Submitted: 2023-04-18
• Last Update Posted: 2023-04-20
• Study Start: 2024-01-01
• Primary Completion: 2026-10-31
• Study Completion: 2027-10-31

Recruitment & Eligibility

• Status: SUSPENDED
• Sex: All
• Target Recruitment: 135

Inclusion Criteria

• Septic shock as defined by the Sepsis-3 criteria
• Septic shock both medical or surgical ethiology (except for re-operation)
• APACHE > 25
• Mechanical ventilation
• Norepinephrine requirement ≥0.4 µg/kg/min for at least 30 minutes, when hypovolemia is highly unlikely as indicated by invasive hemodynamic measurements assessed by the attending physician
• Invasive hemodynamic monitoring to determine cardiac output and derived variables
• Procalcitonin level ≥ 10 ng/ml
• Inclusion within 6 - 24 hours after the onset of vasopressor need and after all standard therapeutic measures have been implemented without clinical improvement (i.e.: the shock is considered refractory)

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Exclusion Criteria

• Patients under 18 years and over 80
• Lack of health insurance
• Pregnancy
• Standard guideline-based medical treatment not exhausted (detailed below at 3.6) standard medical therapy)
• End stage organ failure
• New York Heart Association Class IV.
• Chronic renal failure with eGFR < 15 ml/min/1,73 m2
• End-stage liver disease (MELD score >30, Child-Pugh score Class C
• Unlikely survival for 24 hours according to the attending physician
• Acute onset of hemato-oncological illness
• Post cardiopulmonary resuscitation care
• Re-operation in context with the septic insult
• Immunosuppression
• systemic steroid therapy (>10 mg prednisolon/day)
• immunosuppressive agents (i.e.: methotrexate, azathioprine, cyclosporin, tacrolimus, cyclophosphamide)
• Human immunodeficiency virus infection (active AIDS): HIV-VL > 50 copies/mL
• Patients with transplanted vital organs
• Thrombocytopenia (<20.000/ml)
• More than 10%-of body surface area with a third-degree burn
• Acute coronary syndrome

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A	Standard medical therapy	Patients randomized to standard medical therapy.
Group C	Standard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 24 hours	Patients randomized to cytokine removal therapy with Cytosorb, with the adsorber device changed in every 24 hours.
Group B	Standard medical therapy plus cytokine removal treatment using Cytosorb, with the adsorber changed in every 12 hours	Patients randomized to cytokine removal therapy with Cytosorb, with the adsorber device changed in every 12 hours.

Primary Outcome Measures

Name	Time	Method
Time to shock reversal	From the start of the treatment until shock reversal assessed up to 5 days	The time from the start of the treatment (T0) until shock reversal
Shock reversal	At the time of shock reversal assessed up to 5 days	Proportion of patients achieving shock reversal, defined as follows: no need (or minimal need, meaning max. the 10% of the maximum dose) of vasopressore for 3 hours, with haemodynamic measurements, and arterial, central venous blood gas analysis, arterial lactate level measurement, venous and arterial pCO2-gap and O2 saturation measurements to confirm cardiorespiratory stability

Secondary Outcome Measures

Name	Time	Method
Length of internsive care unit stay	From admission to intensive care unit until the end of intensive care unit assessed at study completion an avarage of 90 days	Length of intensive care unit stay given in days
Change in interleukin-1 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in interleukin-1 level from the start of the treatment until the end of the study period
Interleukin-1ra level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of interleukin-1ra
Interleukin-8 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of interleukin-8
Change in procalcitonine level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in procalcitonine level from the start of the treatment until the end of the study period
Change in interleukin-1ra level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in interleukin-1ra level from the start of the treatment until the end of the study period
Change in interleukin-8 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in interleukin-8 level from the start of the treatment until the end of the study period
Syndecan-1 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of syndecan-1
Change in C-reactive protein level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in C-reactive protein level from the start of the treatment until the end of the study period
Interleukin-1 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of interleukin-1
Change in interleukin-10 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in interleukin-10 level from the start of the treatment until the end of the study period
Change in tumor necrosis factor alpha level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in tumor necrosis factor alpha level from the start of the treatment until the end of the study period
Procalcitonine level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of procalcitonine
Interleukin-6 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of interleukin-6
Change in interleukin-6 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in interleukin-6 level from the start of the treatment until the end of the study period
C-reactive protein level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of C-reactive protein
Interleukin-10 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of interleukin-10
Tumor necrosis factor alpha level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of tumor necrosis factor alpha
Change in arterial lactate levels level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in arterial lactate level from the start of the treatment until the end of the study period
Change in SOFA score	From the start of the treatment until the end of the treatment assessed up to 5 days	Change in SOFA score from the start of the treatment until the end of the study period
Change in extravascular lung water (EVLW)	From the start of the treatment until the end of the treatment assessed up to 5 days	Change in extravascular lung water (EVLW) from the start of the treatment until the end of the study period
Change in syndecan-1 level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in syndecan-1 level from the start of the treatment until the end of the study period
Arterial lactate levels	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of arterial lactate levels
Adverse events	Recorded at the occurrance of adverse events, and study completion up to 90 +/- 7 days	Rate of patients experiencing adverse events, or device deficiencies
Duration of mechanical ventilation	From the start of the treatment until the end of the treatment assessed up to 5 days	Duration of mechanical ventilation given in days
Heparan sulphate level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Absolute level of heparan sulphate
Change in heparan sulphate level	0, 6, 12,24 hours after the start of the treatment, then daily until the end of study period assessed up to 90 +/- 7 days at second follow-up visit	Change in heparan sulphate level from the start of the treatment until the end of the study period
Duration of catecholamine requirement	From the start of the catecholamine requirement until the end of the catecholamine requirement assessed up to 5 days	Duration of catecholamine requirement given in days
Duration of renal replacement therapy	From the start of the renal replacement therapy requirement until the end of the renal replacement therapy requirement assessed up to 90+/-7 days at the second follow-up visit	Duration of renal replacement therapy given in days
Need for dialysis	day 28±7, day 90±7	Rate of patients, who require dialysis
Length of hospital stay	From admission to the hospital until the end of hospital stay assessed at study completion an avarage of 90 days	Length of hospital stay given in days
Survival	Rate if surviving patients assessed at death, or study completion which ever happens first, up to 90 +/-7 days	Rate of surviving patients

Trial Locations

Locations (1)

Institute for Translational Medicine, University of Pécs; 🇭🇺 Pécs, Hungary